Binding agents

Abstract

Compositions and methods relating to epitopes of sclerostin protein, and sclerostin binding agents, such as antibodies capable of binding to sclerostin, are provided.

What is claimed is: 
     
         1 . A sclerostin binding agent that cross-blocks the binding of at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24 to sclerostin. 
     
     
         2 . The sclerostin binding agent of  claim 1  wherein said sclerostin binding agent is cross-blocked from binding to sclerostin by at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24. 
     
     
         3 . A sclerostin binding agent that is cross-blocked from binding to sclerostin by at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24. 
     
     
         4 . The sclerostin binding agent of  claim 1 or 3  wherein the ability of said sclerostin binding agent to cross-block or to be cross-blocked is detected in a Biacore assay. 
     
     
         5 . The sclerostin binding agent of  claim 1 or 3  wherein the ability of said sclerostin binding agent to cross-block or to be cross-blocked is detected in an ELISA assay. 
     
     
         6 . The sclerostin binding agent of  claim 1 or 3  wherein said sclerostin binding agent is an antibody. 
     
     
         7 . The sclerostin binding agent of  claim 1 or 3  wherein said sclerostin binding agent can increase at least one of bone formation, bone mineral density, bone mineral content, bone mass, bone quality and bone strength in a mammal. 
     
     
         8 . The sclerostin binding agent of  claim 1 or 3  wherein said sclerostin binding agent can block the inhibitory effect of sclerostin in a cell based mineralization assay. 
     
     
         9 . A sclerostin binding agent wherein said sclerostin binding agent can block the inhibitory effect of sclerostin in a cell based mineralization assay. 
     
     
         10 . A sclerostin binding agent that binds to a Loop 2 epitope. 
     
     
         11 . A sclerostin binding agent that binds to a T20.6 epitope. 
     
     
         12 . A sclerostin binding agent that binds to a “T20.6 derivative 1 (cystine-knot+4 arms)” epitope. 
     
     
         13 . The sclerostin binding agent of any one of  claims 7-12  wherein said sclerostin binding agent is an antibody. 
     
     
         14 . A sclerostin binding agent that comprises at least one CDR sequence having at least 75% identity to a CDR selected from SEQ ID NOs:39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 78, 79, 80, 81, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 351, 352, 353, 358, 359, and 360. 
     
     
         15 . The sclerostin binding agent of  claim 14  comprising at least two of said CDR's. 
     
     
         16 . The sclerostin binding agent of  claim 14  comprising six of said CDR's. 
     
     
         17 . The sclerostin binding agent according to  claim 14  wherein said percent identity is 85%. 
     
     
         18 . The sclerostin binding agent according to  claim 14  wherein said percent identity is 95%. 
     
     
         19 . The sclerostin binding agent according to  claim 14  comprising:
 a) CDR sequences of SEQ ID NOs:39, 40, and 41; 
 b) CDR sequences of SEQ ID NOs:42, 43, and 44; 
 c) CDR sequences of SEQ ID NOs:45, 46, and 47; 
 d) CDR sequences of SEQ ID NOs:48, 49, and 50; 
 e) CDR sequences of SEQ ID NOs:51, 52, and 53; 
 f) CDR sequences of SEQ ID NOs:54, 55, and 56; 
 g) CDR sequences of SEQ ID NOs:57, 58, and 59; 
 h) CDR sequences of SEQ ID NOs:60, 61, and 62; 
 i) CDR sequences of SEQ ID NOs:275, 276, and 277; 
 j) CDR sequences of SEQ ID NOs:287, 288, and 289; 
 k) CDR sequences of SEQ ID NOs:278, 279, and 280; 
 l) CDR sequences of SEQ ID NOs:290, 291, and 292; 
 m) CDR sequences of SEQ ID NOs:78, 79, and 80; 
 n) CDR sequences of SEQ ID NOs:245, 246, and 247; 
 o) CDR sequences of SEQ ID NOs:81, 99, and 100; 
 p) CDR sequences of SEQ ID NOs:248, 249, and 250 
 q) CDR sequences of SEQ ID NOs:101, 102, and 103; 
 r) CDR sequences of SEQ ID NOs:251, 252, and 253; 
 s) CDR sequences of SEQ ID NOs:104, 105, and 106 
 t) CDR sequences of SEQ ID NOs:254, 255, and 256; 
 u) CDR sequences of SEQ ID NOs:107, 108, and 109 
 v) CDR sequences of SEQ ID NOs:257, 258, and 259 
 w) CDR sequences of SEQ ID NOs: 110, 111, and 112; 
 x) CDR sequences of SEQ ID NOs:260, 261, and 262; 
 y) CDR sequences of SEQ ID NOs:281, 282, and 283; 
 z) CDR sequences of SEQ ID NOs:293, 294, and 295; 
 aa) CDR sequences of SEQ ID NOs: 113, 114, and 115; 
 bb) CDR sequences of SEQ ID NOs:263, 264, and 265; 
 cc) CDR sequences of SEQ ID NOs:284, 285, and 286; 
 dd) CDR sequences of SEQ ID NOs:296, 297, and 298; 
 ee) CDR sequences of SEQ ID NOs:116, 237, and 238; 
 ff) CDR sequences of SEQ ID NOs:266, 267, and 268; 
 gg) CDR sequences of SEQ ID NOs:239, 240, and 241; 
 hh) CDR sequences of SEQ ID NOs:269, 270, and 271; 
 ii) CDR sequences of SEQ ID NOs:272, 273, and 274; 
 jj) CDR sequences of SEQ ID NOs:242, 243, and 244; 
 kk) CDR sequences of SEQ ID NOs:351, 352, and 353; or 
 ll) CDR sequences of SEQ ID NOs:358, 359, and 360. 
 
     
     
         20 . The sclerostin binding agent according to  claim 14  comprising:
 a) CDR sequences of SEQ ID NOs:54, 55, and 56 and CDR sequences of SEQ ID NOs:51, 52, and 53; 
 b) CDR sequences of SEQ ID NOs:60, 61, and 62 and CDR sequences of SEQ ID NOs:57, 58, and 59; 
 c) CDR sequences of SEQ ID NOs:48, 49, and 50 and CDR sequences of SEQ ID NOs:45, 46, and 47; 
 d) CDR sequences of SEQ ID NOs:42, 43, and 44 and CDR sequences of SEQ ID NOs:39, 40, and 41; 
 e) CDR sequences of SEQ ID NOs:275, 276, and 277 and CDR sequences of SEQ ID NOs:287, 288, and 289; 
 f) CDR sequences of SEQ ID NOs:278, 279, and 280 and CDR sequences of SEQ ID NOs:290, 291, and 292; 
 g) CDR sequences of SEQ ID NOs:78, 79, and 80 and CDR sequences of SEQ ID NOs: 245, 246, and 247; 
 h) CDR sequences of SEQ ID NOs:81, 99, and 100 and CDR sequences of SEQ ID NOs:248, 249, and 250; 
 i) CDR sequences of SEQ ID NOs: 101, 102, and 103 and CDR sequences of SEQ ID NOs:251, 252, and 253; 
 j) CDR sequences of SEQ ID NOs:104, 105, and 106 and CDR sequences of SEQ ID NOs:254, 255, and 256; 
 k) CDR sequences of SEQ ID NOs:107, 108, and 109 and CDR sequences of SEQ ID NOs:257, 258, and 259; 
 l) CDR sequences of SEQ ID NOs:110, 111, and 112 and CDR sequences of SEQ ID NOs:260, 261, and 262; 
 m) CDR sequences of SEQ ID NOs:281, 282, and 283 and CDR sequences of SEQ ID NOs:293, 294, and 295; 
 n) CDR sequences of SEQ ID NOs: 113, 114, and 115 and CDR sequences of SEQ ID NOs:263, 264, and 265; 
 o) CDR sequences of SEQ ID NOs:284, 285, and 286 and CDR sequences of SEQ ID NOs:296, 297, and 298; 
 p) CDR sequences of SEQ ID NOs: 116, 237, and 238 and CDR sequences of SEQ ID NOs:266, 267, and 268; 
 q) CDR sequences of SEQ ID NOs:239, 240, and 241 and CDR sequences of SEQ ID NOs:269, 270, and 271; 
 r) CDR sequences of SEQ ID NOs:242, 243, and 244 and CDR sequences of SEQ ID NOs:272, 273, and 274; or 
 s) CDR sequences of SEQ ID NOs:351, 352, and 353 and CDR sequences of SEQ ID NOs:358, 359, and 360. 
 
     
     
         21 . The sclerostin binding agent of any one of  claims 14-20  wherein said sclerostin binding agent is an antibody. 
     
     
         22 . A pharmaceutical composition comprising a sclerostin binding agent according to any one of  claims 1-12 and 14-20 . 
     
     
         23 . The composition of  claim 22  wherein said sclerostin binding agent is an antibody. 
     
     
         24 . A sclerostin binding agent comprising at least one CDR sequence having at least 75% identity to a CDR selected from SEQ ID NOs:245, 246, 247, 78, 79, 80, 269, 270, 271, 239, 240 and 241. 
     
     
         25 . A sclerostin binding agent comprising at least one CDR sequence having at least 75% identity to a CDR selected from CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 wherein CDR-H1 has the sequence given in SEQ ID NO:245 or SEQ ID NO:269, CDR-H2 has the sequence given in SEQ ID NO:246 or SEQ ID NO:270, CDR-H3 has the sequence given in SEQ ID NO:247 or SEQ ID NO:271, CDR-L1 has the sequence given in SEQ ID NO:78 or SEQ ID NO:239, CDR-L2 has the sequence given in SEQ ID NO:79 or SEQ ID NO:240 and CDR-L3 has the sequence given in SEQ ID NO:80 or SEQ ID NO 241. 
     
     
         26 . A sclerostin binding agent according to  claim 25  comprising three CDRs, CDR-H1, CDR-H2 and CDR-H3 wherein
 (a) CDR-H1 is SEQ ID NO:245, CDR-H2 is SEQ ID NO:246 and CDR-H3 is SEQ ID NO:247 or 
 (b) CDR-H1 is SEQ ID NO:269, CDR-H2 is SEQ ID NO:270 and CDR-H3 is SEQ ID NO:271. 
 
     
     
         27 . A sclerostin binding agent according to  claim 25  comprising three CDRs, CDR-L1, CDR-L2 and CDR-L3 wherein
 (a) CDRL1 is SEQ ID NO:78, CDR-L2 is SEQ ID NO:79 and CDR-L3 is SEQ ID NO:80; or 
 (b) CDRL1 is SEQ ID NO:239, CDR-L2 is SEQ ID NO:240 and CDR-L3 is SEQ ID NO:241. 
 
     
     
         28 . A sclerostin binding agent according to  claim 25  comprising six CDRs, CDRH-1, CDR-H2, CDR-H3, CDR-L1 CDR-L2 and CDR-L3 wherein
 (a) CDR-H1 is SEQ ID NO:245, CDR-H2 is SEQ ID NO:246, CDR-H3 is SEQ ID NO:247, CDR-L1 is SEQ ID NO:78, CDR-L2 is SEQ ID NO:79 and CDR-L3 is SEQ ID NO:80; or 
 (b) CDR-H1 is SEQ ID NO:269, CDR-H2 is SEQ ID NO:270, CDR-H3 is SEQ ID NO:271, CDR-L1 is SEQ ID NO:239, CDR-L2 is SEQ ID NO:240 and CDR-L3 is SEQ ID NO:241. 
 
     
     
         29 . The sclerostin binding agent of any one of  claims 24-28  which is an antibody. 
     
     
         30 . The sclerostin binding agent of  claim 29  comprising a heavy chain wherein said heavy chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:333; SEQ ID NO:378; SEQ ID NO:327; SEQ ID NO:329; or SEQ ID NO:366. 
     
     
         31 . The sclerostin binding agent of  claim 29  comprising a light chain wherein said light chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:332; SEQ ID NO:376; SEQ ID NO:314; SEQ ID NO:328; or SEQ ID NO:364. 
     
     
         32 . The sclerostin binding agent of  claim 29  comprising both a heavy chain and a light chain wherein
 (a) the heavy chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:333 and the light chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:332; or 
 (b) the heavy chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:378 and the light chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:376; or 
 (c) the heavy chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:327 and the light chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:314; or 
 (d) the heavy chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:329 and the light chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:328; or 
 (e) the heavy chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:366 and the light chain comprises a polypeptide having at least 85% identity to the sequence given in SEQ ID NO:364. 
 
     
     
         33 . The sclerostin binding agent of any one of  claims 24-32  which comprises a light chain and/or heavy chain constant region. 
     
     
         34 . The sclerostin binding agent of  claim 33  which comprises the IgG4 or the IgG2 constant region. 
     
     
         35 . A sclerostin binding agent having a heavy chain comprising CDR's H1, H2 and H3 and comprising a polypeptide having the sequence provided in SEQ ID NO: 137 or a variant thereof in which said CDR's are at least 75% identical to SEQ ID NO:245, 246 and 247, respectively, and a light chain comprising CDR's L1, L2 and L3 and comprising a polypeptide having the sequence provided in SEQ ID NO:133 or a variant thereof in which said CDR's are at least 75% identical to SEQ ID NO:78, 79 and 80, respectively. 
     
     
         36 . A sclerostin binding agent having a heavy chain comprising CDR's H1, H2 and H3 and comprising a polypeptide having the sequence provided in SEQ ID NO:145 or 392 or a variant thereof in which said CDR's are at least 75% identical to SEQ ID NO:245, 246 and 247, respectively, and a light chain comprising CDR's L1, L2 and L3 and comprising a polypeptide having the sequence provided in SEQ ID NO:141 or a variant thereof in which said CDR's are at least 75% identical to SEQ ID NO:78, 79 and 80, respectively. 
     
     
         37 . A sclerostin binding agent having a heavy chain comprising CDR's H1, H2 and H3 and comprising a polypeptide having the sequence provided in SEQ ID NO:335 or a variant thereof in which said CDR's are at least 75% identical to SEQ ID NO:269, 270 and 271, respectively, and a light chain comprising CDR's L1, L2 and L3 and comprising a polypeptide having the sequence provided in SEQ ID NO:334 or a variant thereof in which said CDR's are at least 75% identical to SEQ ID NO:239, 240 and 241, respectively. 
     
     
         38 . A sclerostin binding agent having a heavy chain comprising CDR's H1, H2 and H3 and comprising a polypeptide having the sequence provided in SEQ ID NO:331 or a variant thereof in which said CDR's are at least 75% identical to SEQ ID NO:269, 270 and 271, respectively, and a light chain comprising CDR's L1, L2 and L3 and comprising a polypeptide having the sequence provided in SEQ ID NO:330 or a variant thereof in which said CDR's are at least 75% identical to SEQ ID NO:239, 240 and 241, respectively. 
     
     
         39 . A sclerostin binding agent having a heavy chain comprising CDR's H1, H2 and H3 and comprising a polypeptide having the sequence provided in SEQ ID NO:345 or 396 or a variant thereof in which said CDR's are at least 75% identical to SEQ ID NO:269, 270 and 271, respectively, and a light chain comprising CDR's L1, L2 and L3 and comprising a polypeptide having the sequence provided in SEQ ID NO:341 or a variant thereof in which said CDR's are at least 75% identical to SEQ ID NO:239, 240 and 241, respectively. 
     
     
         40 . A sclerostin binding agent having a heavy chain comprising a polypeptide having the sequence provided in SEQ ID NO:137, and a light chain comprising a polypeptide having the sequence provided in SEQ ID NO:133. 
     
     
         41 . A sclerostin binding agent having a heavy chain comprising a polypeptide having the sequence provided in SEQ ID NO: 145 or 392, and a light chain comprising a polypeptide having the sequence provided in SEQ ID NO: 141. 
     
     
         42 . A sclerostin binding agent having a heavy chain comprising a polypeptide having the sequence provided in SEQ ID NO:335, and a light chain comprising a polypeptide having the sequence provided in SEQ ID NO:334. 
     
     
         43 . A sclerostin binding agent having a heavy chain comprising a polypeptide having the sequence provided in SEQ ID NO:331, and a light chain comprising a polypeptide having the sequence provided in SEQ ID NO:330. 
     
     
         44 . A sclerostin binding agent having a heavy chain comprising a polypeptide having the sequence provided in SEQ ID NO:345 or 396, and a light chain comprising a polypeptide having the sequence provided in SEQ ID NO:341. 
     
     
         45 . A sclerostin binding agent according to any one of  claims 24-44  to which one or more effector or reporter molecule(s) is attached. 
     
     
         46 . An isolated polynucleotide sequence encoding the sclerostin binding agent according to any one of  claims 24-44 . 
     
     
         47 . A cloning or expression vector comprising one or more polynucleotide sequences according to  claim 46 . 
     
     
         48 . A vector according to  claim 47 , wherein the vector comprises at least one sequence given in SEQ ID NO:134, 136, 138, 140, 142, 144, 146, 148, 308, 310, 312, 342, 344, 346, 348, 349, 365, 367, 373, 375, and 379. 
     
     
         49 . A host cell comprising one or more cloning or expression vectors according to  claim 47 or claim 48 . 
     
     
         50 . A process for the production of the sclerostin binding agent of any one of  claims 24-44 , comprising culturing the host cell of  claim 49  and isolating the sclerostin binding agent. 
     
     
         51 . A pharmaceutical composition comprising a sclerostin binding agent according to any one of  claims 24-45  in combination with one or more of a pharmaceutically acceptable excipient, diluent or carrier. 
     
     
         52 . A pharmaceutical composition according to  claim 51 , additionally comprising other active ingredients. 
     
     
         53 . A sclerostin binding agent according to any one of  claims 24-45  or a pharmaceutical composition according to  claim 51 or claim 52 , for use in the treatment or prophylaxis of a pathological disorder that is mediated by sclerostin or that is associated with an increased level of sclerostin. 
     
     
         54 . A method for treating a bone-related disorder in a mammalian subject which comprises providing to a subject in need of such treatment a pharmaceutical composition of  claim 22 . 
     
     
         55 . A method for treating a bone-related disorder in a mammalian subject which comprises providing to a subject in need of such treatment a pharmaceutical composition of  claim 23 . 
     
     
         56 . A method for treating a bone-related disorder in a mammalian subject which comprises providing to a subject in need of such treatment a pharmaceutical composition of  claim 51 . 
     
     
         57 . The method according to  claim 54 , wherein the bone-related disorder is at least one of achondroplasia, cleidocranial dysostosis, enchondromatosis, fibrous dysplasia, Gaucher's Disease, hypophosphatemic rickets, Marfan's syndrome, multiple hereditary exotoses, neurofibromatosis, osteogenesis imperfecta, osteopetrosis, osteopoikilosis, sclerotic lesions, pseudoarthrosis, pyogenic osteomyelitis, periodontal disease, anti-epileptic drug induced bone loss, primary and secondary hyperparathyroidism, familial hyperparathyroidism syndromes, weightlessness induced bone loss, osteoporosis in men, postmenopausal bone loss, osteoarthritis, renal osteodystrophy, infiltrative disorders of bone, oral bone loss, osteonecrosis of the jaw, juvenile Paget's disease, melorheostosis, metabolic bone diseases, mastocytosis, sickle cell anemia/disease, organ transplant related bone loss, kidney transplant related bone loss, systemic lupus erythematosus, ankylosing spondylitis, epilepsy, juvenile arthritides, thalassemia, mucopolysaccharidoses, Fabry Disease, Turner Syndrome, Down Syndrome, Klinefelter Syndrome, leprosy, Perthes' Disease, adolescent idiopathic scoliosis, infantile onset multi-system inflammatory disease, Winchester Syndrome, Menkes Disease, Wilson's Disease, ischemic bone disease (such as Legg-Calve-Perthes disease, regional migratory osteoporosis), anemic states, conditions caused by steroids, glucocorticoid-induced bone loss, heparin-induced bone loss, bone marrow disorders, scurvy, malnutrition, calcium deficiency, osteoporosis, osteopenia, alcoholism, chronic liver disease, postmenopausal state, chronic inflammatory conditions, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, inflammatory colitis, Crohn's disease, oligomenorrhea, amenorrhea, pregnancy, diabetes mellitus, hyperthyroidism, thyroid disorders, parathyroid disorders, Cushing's disease, acromegaly, hypogonadism, immobilization or disuse, reflex sympathetic dystrophy syndrome, regional osteoporosis, osteomalacia, bone loss associated with joint replacement, HIV associated bone loss, bone loss associated with loss of growth hormone, bone loss associated with cystic fibrosis, chemotherapy associated bone loss, tumor induced bone loss, cancer-related bone loss, hormone ablative bone loss, multiple myeloma, drug-induced bone loss, anorexia nervosa, disease associated facial bone loss, disease associated cranial bone loss, disease associated bone loss of the jaw, disease associated bone loss of the skull, bone loss associated with aging, facial bone loss associated with aging, cranial bone loss associated with aging, jaw bone loss associated with aging, and skull bone loss associated with aging and bone loss associated with space travel. 
     
     
         58 . The method according to  claim 55 , wherein the bone-related disorder is at least one of achondroplasia, cleidocranial dysostosis, enchondromatosis, fibrous dysplasia, Gaucher's Disease, hypophosphatemic rickets, Marfan's syndrome, multiple hereditary exotoses, neurofibromatosis, osteogenesis imperfecta, osteopetrosis, osteopoikilosis, sclerotic lesions, pseudoarthrosis, pyogenic osteomyelitis, periodontal disease, anti-epileptic drug induced bone loss, primary and secondary hyperparathyroidism, familial hyperparathyroidism syndromes, weightlessness induced bone loss, osteoporosis in men, postmenopausal bone loss, osteoarthritis, renal osteodystrophy, infiltrative disorders of bone, oral bone loss, osteonecrosis of the jaw, juvenile Paget's disease, melorheostosis, metabolic bone diseases, mastocytosis, sickle cell anemia/disease, organ transplant related bone loss, kidney transplant related bone loss, systemic lupus erythematosus, ankylosing spondylitis, epilepsy, juvenile arthritides, thalassemia, mucopolysaccharidoses, Fabry Disease, Turner Syndrome, Down Syndrome, Klinefelter Syndrome, leprosy, Perthes' Disease, adolescent idiopathic scoliosis, infantile onset multi-system inflammatory disease, Winchester Syndrome, Menkes Disease, Wilson's Disease, ischemic bone disease (such as Legg-Calve-Perthes disease, regional migratory osteoporosis), anemic states, conditions caused by steroids, glucocorticoid-induced bone loss, heparin-induced bone loss, bone marrow disorders, scurvy, malnutrition, calcium deficiency, osteoporosis, osteopenia, alcoholism, chronic liver disease, postmenopausal state, chronic inflammatory conditions, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, inflammatory colitis, Crohn's disease, oligomenorrhea, amenorrhea, pregnancy, diabetes mellitus, hyperthyroidism, thyroid disorders, parathyroid disorders, Cushing's disease, acromegaly, hypogonadism, immobilization or disuse, reflex sympathetic dystrophy syndrome, regional osteoporosis, osteomalacia, bone loss associated with joint replacement, HIV associated bone loss, bone loss associated with loss of growth hormone, bone loss associated with cystic fibrosis, chemotherapy associated bone loss, tumor induced bone loss, cancer-related bone loss, hormone ablative bone loss, multiple myeloma, drug-induced bone loss, anorexia nervosa, disease associated facial bone loss, disease associated cranial bone loss, disease associated bone loss of the jaw, disease associated bone loss of the skull, bone loss associated with aging, facial bone loss associated with aging, cranial bone loss associated with aging, jaw bone loss associated with aging, skull bone loss associated with aging, and bone loss associated with space travel. 
     
     
         59 . The method according to  claim 56 , wherein the bone-related disorder is at least one of achondroplasia, cleidocranial dysostosis, enchondromatosis, fibrous dysplasia, Gaucher's Disease, hypophosphatemic rickets, Marfan's syndrome, multiple hereditary exotoses, neurofibromatosis, osteogenesis imperfecta, osteopetrosis, osteopoikilosis, sclerotic lesions, pseudoarthrosis, pyogenic osteomyelitis, periodontal disease, anti-epileptic drug induced bone loss, primary and secondary hyperparathyroidism, familial hyperparathyroidism syndromes, weightlessness induced bone loss, osteoporosis in men, postmenopausal bone loss, osteoarthritis, renal osteodystrophy, infiltrative disorders of bone, oral bone loss, osteonecrosis of the jaw, juvenile Paget's disease, melorheostosis, metabolic bone diseases, mastocytosis, sickle cell anemia/disease, organ transplant related bone loss, kidney transplant related bone loss, systemic lupus erythematosus, ankylosing spondylitis, epilepsy, juvenile arthritides, thalassemia, mucopolysaccharidoses, Fabry Disease, Turner Syndrome, Down Syndrome, Klinefelter Syndrome, leprosy, Perthes' Disease, adolescent idiopathic scoliosis, infantile onset multi-system inflammatory disease, Winchester Syndrome, Menkes Disease, Wilson's Disease, ischemic bone disease (such as Legg-Calve-Perthes disease, regional migratory osteoporosis), anemic states, conditions caused by steroids, glucocorticoid-induced bone loss, heparin-induced bone loss, bone marrow disorders, scurvy, malnutrition, calcium deficiency, osteoporosis, osteopenia, alcoholism, chronic liver disease, postmenopausal state, chronic inflammatory conditions, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, inflammatory colitis, Crohn's disease, oligomenorrhea, amenorrhea, pregnancy, diabetes mellitus, hyperthyroidism, thyroid disorders, parathyroid disorders, Cushing's disease, acromegaly, hypogonadism, immobilization or disuse, reflex sympathetic dystrophy syndrome, regional osteoporosis, osteomalacia, bone loss associated with joint replacement, HIV associated bone loss, bone loss associated with loss of growth hormone, bone loss associated with cystic fibrosis, chemotherapy associated bone loss, tumor induced bone loss, cancer-related bone loss, hormone ablative bone loss, multiple myeloma, drug-induced bone loss, anorexia nervosa, disease associated facial bone loss, disease associated cranial bone loss, disease associated bone loss of the jaw, disease associated bone loss of the skull, bone loss associated with aging, facial bone loss associated with aging, cranial bone loss associated with aging, jaw bone loss associated with aging, skull bone loss associated with aging, and bone loss associated with space travel. 
     
     
         60 . A method of increasing at least one of bone formation, bone mineral content, bone mass, bone mineral density, bone quality, and bone strength in a mammal comprising administering to the mammal a pharmaceutical composition of  claim 22 . 
     
     
         61 . A method of increasing at least one of bone formation, bone mineral content, bone mass, bone mineral density, bone quality, and bone strength in a mammal comprising administering to the mammal a pharmaceutical composition of  claim 23 . 
     
     
         62 . A method of increasing at least one of bone formation, bone mineral content, bone mass, bone mineral density, bone quality, and bone strength in a mammal comprising administering to the mammal a pharmaceutical composition of  claim 51 . 
     
     
         63 . A method of improving the outcome in a mammal undergoing one or more of an orthopedic procedure, dental procedure, implant surgery, joint replacement, bone grafting, bone cosmetic surgery and bone repair such as fracture healing, nonunion healing, delayed union healing and facial reconstruction, comprising administering to said mammal a pharmaceutical composition of  claim 22  before, during and/or after said procedure, replacement, graft, surgery or repair. 
     
     
         64 . A method of improving the outcome in a mammal undergoing one or more of an orthopedic procedure, dental procedure, implant surgery, joint replacement, bone grafting, bone cosmetic surgery and bone repair such as fracture healing, nonunion healing, delayed union healing and facial reconstruction, comprising administering to said mammal a pharmaceutical composition of  claim 23  before, during and/or after said procedure, replacement, graft, surgery or repair. 
     
     
         65 . A method of improving the outcome in a mammal undergoing one or more of an orthopedic procedure, dental procedure, implant surgery, joint replacement, bone grafting, bone cosmetic surgery and bone repair such as fracture healing, nonunion healing, delayed union healing and facial reconstruction, comprising administering to said mammal a pharmaceutical composition of  claim 51  before, during and/or after said procedure, replacement, graft, surgery or repair. 
     
     
         66 . An antibody, wherein said antibody is Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, or Ab-24. 
     
     
         67 . A diagnostic kit comprising a sclerostin binding agent according to any one of  claims 1, 3, 9-12 and 14-20 . 
     
     
         68 . A diagnostic kit comprising an antibody according to  claim 6 . 
     
     
         69 . A diagnostic kit comprising an antibody according to  claim 21 . 
     
     
         70 . A diagnostic kit comprising an antibody according to  claim 29 . 
     
     
         71 . A polypeptide comprising at least one of SEQ ID NOs:39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 78, 79, 80, 81, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 351, 352, 353, 358, 359, and 360. 
     
     
         72 . A polypeptide according to  claim 71  conjugated to at least one of Fc, PEG, albumin, and transferrin.